Inherited and sporadic retinal degeneration leads to vision loss in hundreds of thousands of people each year. Like many neuronal degenerative diseases, the end result of retinal degeneration is the activation of a cell death pathway termed apoptosis. In humans, and in other model systems, many mutations have been identified that cause retinal degeneration. However, how these molecular defects eventually engage the apoptotic machinery is unknown in nearly all cases. Our laboratory uses the fruit fly Drosophila melanogaster as a model system to study retinal degeneration. In particular we focus on one form of retinal degeneration where the light receptor rhodopsin is internalized from the plasma membrane to the cytoplasm where it aggregates and eventually triggers photoreceptor cell apoptosis. Recently, we have demonstrated that a class of proteases called cathepsins is instrumental in this degenerative process, implicating them as a possible link between specific mutations in the photoreceptor cell and apoptotic cell death. In this grant we plan to investigate the role of cathepsins in retinal degeneration by: 1) testing whether cathepsins exhibit intracellular translocation during the retinal degeneration process, 2) examining the effect of specific mutations in cathepsins on retinal degeneration, and 3) testing whether a key cathepsin substrate is cleaved during retinal degeneration. Cathepsins have never been implicated in retinal degeneration, and therefore this work will provide a novel molecular mechanism for photoreceptor cell degeneration. Moreover, since there are numerous cathepsin inhibitors available, there is the possibility that this work could provide potential therapies for retinal disease. [unreadable] [unreadable] [unreadable]